4-alkyl-1, 4-dimethylcyclohex-ylamines and 4-alkyl-1, 4-dimethylcyclohexanemethylamines



United States PatentO 1 3,392,198 r 4 ALKYL 1,4 DIMETHYLCYCLOHEX- YLAMINES AND .4-ALKYL-1,4-DIMETH- YLCYCLOHEXANEMETHYLAMINES Marvin Paulshock, Wilmington, DeL, assignor to E. I. du Pont de Nemours and Company, Wilmington, DelL, a corporation of Delaware I No Drawing. Filed May 26, 1964, Ser. No. 370,372 r 16 Claims. (Cl. 260-563) ABSTRACT OF THE DISCLOSURE 4-alkyl-l,4-dimethylcyclohexylamines and 4-alkyl-l,4 dimethylcyclohexanemethylamines exhibit valuable pharmaceutical properties and in particular exhibit significant antiviral activity.

This invention relates to tetrasubstituted cyclohexanes.

More particularly, this invention refers to novel 4-alkyl- 1,4-dimethylcyclohexylamines and 4-alkyl-1,4-dimethylcyclohexanemethylamines and to pharmaceutical compositions and methods utilizing such compounds.

The compounds of the present invention can be represented by the formula I where R is methyl, ethyl, propyl or isopropyl;

X and Y are each hydrogen, methyl, or ethyl;

n is either or 1; and

wherein R is hydrogen, alkyl or 1 through 4 carbon atoms, alkenyl of 3 through 4 carbon atoms, or alkynyl of 3 through 4 carbon atoms with the proviso that for said alkenyl and said alkynyl the unsaturated bonding is other than in the 1-position;

R is R or formyl; and

R is aliphatic; monosubstituted aliphatic where the substituent is aromatic or heterocyclic; aromatic; or heterocyclic containing not more than 12 carbon atoms.

Compounds of Formula 1 where R is other than methyl can exist as cis isomers; trans isomers, and mixtures of the two. Compounds hydrolyzable to the compounds of Formula 1 are for the most purposes equivalent to those compounds and are therefore contemplated as within the scope of the present invention.

It also will be understood that the compounds of Formula 1, having a basic amino group, readily form salts with acids and such salts havinga nontoxic anion are also included within the scope of the present invention. Representative of such salts are hydrochlorides, hydrobromides, sulfates, phosphates, nitrites, acetates, succinates, adipates, propionates, tartrates, citrates, bicarbonates, pamoates, cyclohexylsulfamates, and acetylsalicylates. Of these the hydrochlorides, acetates and cyclohexylsulfamates are preferred. The cyclohexylsulfamates have a pleasant taste and thus are particularly useful in preparing syrups for oral administration. Additionally, the cyclohexylsulfamates have usefulness in making uncoated tablets for oral administration which have no objectionable bitter taste.

Compounds within the scope of Formula 1 exhibit valuable pharmaceutical properties and in particular an ability to deter and inhibit incidence and growth of harmful ice viruses. An unusually high anti-viral potency and favorable therapeutic ratio has been noted in animal tests. For example, in vivo tests in mice have demonstrated such activity against the virus strain influenza A (8-15). Additionally, it has been found that compounds of the invention exhibit significant stimulant activity.

Within the overall scope of the compounds of the invention, various subclasses of compounds are found to provide particularly useful combinations of properties. For example, by proper selection of compounds, it is found that it is possible to attain different desired balancesof stimulant and antiviral activities as well as diffunction from the cyclohexyl ring (compounds where n:l) also offer good antiviral activity combined with reduced stimulant activity. Most preferred for cases where stimulation must be suppressed to the utmost are the N,N- dialkylated aminomethyl compounds of the invention or compounds of the formula I CH3 R where R, X and Y are defined as before in Formula 1.

Preferred compounds of the invention from the standpoint of favorable drug dynamics, chiefly longer acting prior to degradation or excretion are a, u-substituted methylamino derivatives or compounds of the formula where R, R and R are defined as before in Formula 1 and X and Y are each methyl or ethyl.

Preferred compounds of the invention for potency of antiviral activity are those in which R is methyl. Particularly preferred of this class of compounds due to outstanding antiviral activity and economy of manufacture is l,4,4-trimethylcyclohexylamine.

In view of the foregoing considerations, preferred compounds of the invention for pharmaceutical application are the hydrochlorides of the following compounds:

l,4,4-trimethylcyclohexylamine hydrochloride N,N-1,4,4-pentamethylcyclohexylamine hydrochloride N-l,4,4-tetramethylcyclohexylamine hydrochloride 1,4,4-trimethylcyclohexanemethylamine hydrochloride N,N-1,4,4-pentamethylcyclohexanemethylamine hydrochloride N-l,4,4-tetramethylcyclohexanemethylamine hydrochloride 4-ethyl-1,4-dimethylcyclohexylamine hydrochloride 4-ethyl-N,N-l,4-tetramethylcyclohexylamine hydrochloride 4-ethyl-N-1,4-trimethylcyclohexylamine hydrochloride a-l,4,4-tetramethylcyclohexanemethylamine hydrochloride N,N-a-l,4,4-hexamethylcyclohexanemethylamine hydrochloride a,a-1,4,4-pentamethylcyclohexanemethylamine hydrochloride N,N-a, x-l,4,4-heptamethylcyclohexanemethylamine hydrochloride The compounds of the invention can be prepared by a variety of methods such as will be obvious from the following discussion.

To synthesize 4-alkyl-1,4-dimethylcyclohexylamines, one subjects a 4-alkyl-1,4-dimethylcyclohexanol to the Ritter reaction, using acetonitrile and sulfuric acid or hydrogen cyanide and sulfuric acid to yield the N-acetyl or N-formyl-4-alkyl-1,4-dimethylcyclohexylamine. The acetyl or formyl group is removed by alkaline hydrolysis to yield the 4-alkyl-1,4-dimethylcyclohexylamine.

For the synthesis of 4-alkyl-l,4-dimethylcyclohexanemethylamines, one first converts a 4-alkyl-1,4-dimethylcyclohexanol to the 4-alkyl-1,4-dimethylcyclohexanecarboxylic acid by the action of formic acid and sulfuric acid, then converts the carboxylic acid to the acid chloride with thionyl chloride or phosphorus pentachloride, and prepares the carboxamide by reaction with ammonia. Reduction of the 4-alkyl-l,4-dimethylcyclohexanecarboxamide with lithium aluminum hydride or by catalytic reduction yields the 4-alkyl-l,4-dimethylcyclohexanemethylamine.

In preparing u-alkyl-4-alkyl-1,4-dimethylcyclohexanemethylamines one converts a 4-alkyl-1,4-dimetl1ylcyclohexanecarboxylic acid chloride to a 4-alkyl-l,4-dimethylcyclohexyl-(l) alkyl ketone by the action of ethoxymagnesium diethyl malonate or a dialkyl cadmium. The ketone is converted to the oxime, and the oxime is reduced catalytically or within lithium aluminum hydride to give the a-alkyl-4-alkyl-1,4-dimethylcyclohexanemethylamine.

The 4-alkyl-l,4-dimethylcyclohexyl-(1) alkyl ketones are used as starting materials for preparation of ot-alkyl-ocalkyl 4 alkyl 1,4 dimethylcyclohexanemethylamines. By the action of the appropriate alkyl Grignard reagent, the ketone is converted to an a-alkyl-u-alkyl-4-alkyl-1,4- dimethylcyclohexanemethanol. A Ritter reaction on this compound produces an N-acetyl or N-formyl-a-alkyl-aalkyl 4 alkyl 1,4 dimethylcyclohexanemethylamine, from which the ot-alkyl-u-alkyl-4-alkyl-1,4-dimethylcyclohexanemethylamine is liberated by alkaline hydrolysis. It is evident that different a-alkyl groups can be introduced by this synthesis.

The cylclohexylamines and cyclohexanemethylamines of this invention can be N-alkylated by acylation and reduction. That is, the primary amine can be acylated with an acid chloride, acid anhydride or ester to give the N-acyl compound, which is reduced with lithium aluminum hydride or by catalytic hydrogenation to give the N-alkyl compound. For example, reaction of butyryl chloride in pyridine with 1,4,4-trimethylcyclohexylamine yields N- butyryl-l,4,4-trimethylcyclohexylamine. Lithium aluminum hydride reduction of this compound yields N-butyl- 1,4,4-trimethylcyclohexylamine. Reductions of intermediates from the Ritter reaction yield N-ethyl and N-methyl amines.

N-alkylamines can be acylated again and reduced to yield N,N-dialkylamines. Thus, N,N-dialkylamines having different alkyl groups can be prepared by the use of different acylating agents, or N,N-dialkylamines having like alkyl groups can be prepared by using the same acylating agent for the first and second acylations.

While reduction of an N-formylamine from the Ritter reaction (or made by formylation of the primary amine with butyl formate, for example) followed by another formylation and reduction is a perfectly practical method for obtaining the N,N-dimethylamine compound, it is easier to use the Eschweiler-Clarke reaction of formic acid and formaldehyde with the primary amine to obtain the N,N-dimethylamine. In fact, where one of the alkyl groups of an N,N-dialkylamine is methyl, it is easiest to introduce the non-methyl alkyl group by acylation and reduction and then to treat this with formic acid and formaldehyde to obtain the N-alkyl-N-methylamine.

In preparing N-alkyl and N,N-dialkyl-4-alkyl-1,4-dimethylcyclohexanemethylamines, it is not necessary to prepare the primary amine and then alkylate it in subsequent steps. If an alkylamine or dialkylamine is used instead of ammonia in the reaction of 4-alkyl-l,4-dimethyl-cyclohexanecarboxylic acid chlorides to form the carboxamides, N-alkyl or N,N-dialkyl-4-alkyl-1,4-dimethylcyclohexanecarboxamides are formed, which, when reduced, yield N-alkyl and N,N-dialkyl-4-alkyl-1,4-dimethylcyclohexanemethylamines directly. If the carboxamide having mixed N,N-dialkyl groups is prepared by using a dialkylamine having different alkyl groups, an N,N-dialkylcyclohexanemethylamine having dilferent N-alkyl groups is obtained.

N-alkenyl and N-alkynyl groups are best introduced by direct alkylation, using an alkenyl or alkynyl halide and an acid acceptor such as sodium bicarbonate. When equimolar quantities of the primary and the halide are used, the major product is the N-alkenyl or N-alkynylamine, but usually some of the N,N-dialkenyl or N,N-dialkynylamine is formed as a byproduct. The two can usually be separated by distillation. If an N-alkyl-N- alkenyl or N-alkyl-N-alkynylamine is desired, one starts with the N-alkylamine and introduces the alkenyl or alkynyl group, again using an equimolar amount of the halide. Excess halide should be avoided. If the reactions of primary amines excess halide leads to di-alkenylation and di-alkynylation. With secondary amines it leads to quaternization, decreasing the yield of the desired product.

Salts of the amines of this invention can be prepared in a number of ways. Generally, the amine is contacted with the acid in water or in an organic solvent. In some instances, the salt is insoluble, and is filtered and dried. For example, most of the hydrochlorides of amines of this invention are insoluble in ether. Solvents such as alcohol and water, in which the amine salts are generally soluble, can be used just as well. After the amine and the acid have been combined, the solvent is removed by evaporation.

Because solubility of the salt in Water depends to an extent on the acid anion, many salts are in fact insoluble in water and alcohols. Pamoates, for example, are usually quite water-insoluble and separate from aqueous mixtures almost quantitatively.

The following amines and their salts are representative of the compounds of this invention:

1,4,4-trimethylcyclohexylamine N- l ,4,4-tetramethylcyclohexylamine N,N- l ,4,4-pentamethylcyclyohexylamine 1,4,4-trimethylcyclohexanemethylamine N- l ,4,4-tetramethylcyclohexanemethylamine N,N-1,4,4-pentamethylcyclohexanemethylamine a-1,4,4-tetramethylcyclohexanemethylamine N-ocl ,4,4-pentamethylcyclohexanemethylamine N,N-m-1,4,4-hexamethylcyclohexanemethylamine oz,oz- 1,4,4-pentamethylcyclohexanemethylamine N-a,a-1,4,4-hexanemethylcyclohexanemethylamine N,N-a,a-1,4,4-heptamethylcyclohexanemethylamine 4-ethyl-1,4-dimethylcyclohexylamine 4-isopropyl-1,4-dimethylcyclohexanemethylamine 4-propyl-al ,4-trimethylcyclohexanemethylamine ot-Ethyll ,4,4-trimethylcyclohexanemethylamine u-4-diethyl-a- 1 ,4-trimethylcyclohexanemethylamine a,a-4-triethyl-1,4-dimethylcyclohexanemethylamine N-ethyl-1,4,4-trimeth ylcyclohexylamine N-propyl-1,4,4ftrimethylcyclohexanemethylamine 4-ethyl-N-isopropyl-a-1,4-trimethylcyclohexanemethylamine N-butyl-a,a-1,4,4-pentamethylcyclohexanemethylamine N-sec-butyl-1,4,4-trimethylcyclohexylamine N-ethyl-N-1,4,4-tetramethylcyclohexylamine N,N-dibutyl-4-propyl-a,a-diethyl-1,4-dimethylcyclohexanemethylamine N-allyl-1,4,4-trimethylcyclohexylamine N-(Z-butenyl)-N-1,4,4-tetramethylcyclohexylamine N-propargyl-4-propyl-1,4-dimethylcyclohexanemethylamine N-( 3-butynyl)-a-N-1,4,4-pentamethylcyclohexanemethylamine The following are representative of the N-formyl compounds of this invention:

N-formyl-1,4,4trimethylcyclohexylamine N-formy1-4-ethyl-1,4-dimethylcyclohexylamine N-formyl-4-isopropyl-1,4-dimethylcyclohexylamine N-formyl-4-propyl-1,4-dimethylcyclohexylamine N-formyl-1,4,4-trimethylcyclohexanemethylamine N-formyl-4-ethyl-1,4-dimethylcyclohexanemethylamine N-formyl-a-1,4,4-tetramethylcyclohexanemethylamine N-formyl-a-4-diethyl-a-1,4-trimethylcyclohexanemethylamine EXAMPLE 1 A 500-ml. round-bottom flask was fitted with stirrer, thermometer, condenser and dropping funnel and dried by heating with a flame under a current of dry nitrogen. The apparatus was cooled, 3.6 g. of magnesium turnings was charged, and a solution of 23 g. of methyl iodide in 100 ml. of ether was added dropwise over about 1 hour. Then, 12.6 g. of 4,4-dimethylcyclohexanone (R. A. Benkeser and E. W. Bennett, J. Am. Chem. Soc., 80, 5414 (1958)) dissolved in 100 ml. of ether was added at reflux over about 1 hour, and the reaction mixture was heated at reflux for 1%. hours after addition was complete. The suspension was poured into 225 g. of ice in a solution of 25 g. of ammonium chloride in 100 ml. of water. The ether layer was separated and the aqueous layer was extracted with three 50-ml. portions of ether. The ether extracts were combined, dried with anhydrous calcium sulfate, and the ether was evaporated to give a white, soapy solid residue of 1,4,4-trimethylcyclohexanol, M.P. 55-58 C. The yield was 13- g., 91.5%. An analytical sample was purified by sublimation.

Analysis.-Calcd for C H Oz C, 75.99; H, 12.76. Found: C, 75.48; H, 12.34.

A 300-ml. round-bottom flask was fitted With stirrer, condenser and thermometer and charged with a solution of 7.1 g. of 1,4,4-trimethylcyclohexanol in 50 ml. of acetonitrile. Then, 50 ml. of concentrated sulfuric acid was added slowly from the dropping funnel, keeping the temperature between 55 and 60 C. The mixture was heated at 55-60 C. for two hours after addition was complete and was then cooled, and allowed to stir at room temperature overnight. It was poured into 200 ml. of ice water, and the resulting solids were filtered and dried to give 7.1 g. of N-acetyl-l,4,4-trimethylcyclohexylamine, M.P. 103-104.5 C. An analytical sample Was purified by recrystallization from hexane. This melted at 107.5109 C.

Analysis.--Calcd for C H NO: C, 72.08; H, 11.55; N, 7.64. Found: C, 71.89; H, 11.25; N, 7.96.

A mixture of 21 ml. of a solution of g. of potassium hydroxide in 26.5 ml. of methanol and 1.5 g. of N-acetyl-1,4,4-trimethylcyclohexylamine was heated 18 hours at 225 C. in a sealed tube. After cooling the tube was opened, 100 ml. of 50% potassium hydroxide was added, and the mixture was extracted with five 50- ml. portions of ether. The ether extracts were combined, dried with potassium hydroxide pellets, and hydrogen chloride gas was bubbled in to the dry solution for 4 minutes. Removal of the ether by evaporation in a vacuum gave 1.2 g. of 1,4,4-trimethylcyclohexylamine hydrochloride, M.P. 232-234" C.

Analysis.--Calcd for C H CIN: C, 60.83; H, 11.35; N, 7.88. Found: C, 60.87; H, 11.32; N, 8.31..

EXAMPLE 2 An 0.05-mole amount of 1,4,4-trimethylcyclohexylamine hydrochloride is converted to the free base by treatment with excess 50% sodium hydroxide solution, extraction of the free base with ether, and removal of the ether by vacuum concentration. The residue, 1,4,4-trimethylcyclohexylamine, is refluxed 19 hours in 25 ml. of butyl formate. The mixture is cooled, the excess butyl formate is removed by vacuum concentration, and the residue is dried to yield N-formyl-1,4,4-trimethylcyclohexylamine.

EXAMPLE 3 An 0.05 mole amount of N-formyl-l,4,4-trimethylcyclohexylamine is dissolved in 200 ml. of dry tetrahydrofuran, and added to a suspension of 3.0 g. of lithium aluminum hydride in 350 ml. of dry ether. After complete addition the mixture is refluxed 1 hour, then cooled to room temperature and water is added to the mixture cautiously until the hydrogen evolution due to destruction of the excess lithium aluminum hydride ceases and the solids become white. This requires about 10 ml. of water. The mixture is stirred 1 hour, then the solids are filtered and washed well with 50 ml. of ether. The filtrate and washings are combined and evaporated in a vacuum. The residue is dissolved in 75 m1. of ether, the ether solution is dried with anhydrous potassium carbonate, and it is then treated with hydrogen chloride gas until precipitation is complete. The precipitate of N-1,4,4- tetramethylcyclohexylamine hydrochloride is filtered and dried.

EXAMPLE 4 The 0.05 mole amount of N-formyl-l,4,4-trimethylcyclohexylamine used in Example 3 is replaced with 0.05 mole of N-acetyl-1,4,4-trimethylcyclohexylamine (Example 1) and Example 3 is repeated to yield N-ethyl- 1,4,4-trimethylcyclohexylamine hydrochloride.

EXAMPLE 5 A SO-ml. round-bottom flask is charged with 0.15 mole (6.90 g.) of 98% formic acid and 0.15 mole (12.1 g.) of 37% formalin solution. Then, 0.05 mole of 1,4,4-trimethylcyclohexylamine (Example 1) is charged, a condenser is attached, and the mixture is heated at with a steam bath for 16 hours. Gas is evolved during the heatup period and for some time thereafter. After cooling, the

EXAMPLE 6 Repetition of the procedure of Example 5, using 0.05 mole of N-ethyl-1,4,4-trimethylcycylohexylamine (Example 4) lnstead of the 0.05 mole of 1,4,4-trimethylcyclohexylamine, yields N-ethyl-N-1,4,4tertramethylcylohexylamine hydrochloride.

EXAMPLE 7 N butyryl-1,4,4-trimethylcyclohexylamine is prepared by dissolving 0.10 mole of l,4,4-trimethylcyclohexylamine in 75 ml. of pyridine and adding 0.15 mole of butyryl chloride dropwise over a 15-minute period with cooling so that the temperature does not rise over 60 C. The mixture is heated at 60 C. for 2 hours, and then cooled and poured into 1000 ml. of ice water. The precipitate of N-butyryl-l,4,4-trimethylcyclohexylamine is filtered and dried.

The 0.05 mole amount of N-formyl-l,4,4-trimethylcyclohexylamine used in Example 3 is replaced with 0.05 mole of N-butyryl-l,4,4-trimethylcyclohexylamine, and Example 3 is repeated to yeild N-butyl-1,4,4-trimethylcyclohexylamine hydrochloride.

EXAMPLE 8 A 2-liter round-bottom flask is equipped with thermometer, dropping funnel, reflux condenser, paddle stirrer and a connection to a gas meter, and charged with 500 ml. of absolute ethanol, 50.4 g. (0.60 mole) of sodium bicarbonate and 0.20 mole of 1,4,4-trimethylcyclohexylamine hydrochloride. Then, 24.2 g. (0.20 mole) of allyl bromide are added from the dropping funnel. There is no appreciable evolution of carbon dioxide. The mixture is gradually warmed to 65 C. whereupon gas evolution begins. The reaction is allowed to proceed until no more gas is evolved. The mixture is cooled, the solids are filtered, and the filtrate is evaporated. The residue is distributed between ether and sodium hydroxide solution. The ether layer is dried with anhydrous potassium carbonate and evaporated. The residue is distilled at reduced pressure to give two main fractions. The lower-boiling fraction is N-allyl-1,4,4-trimethylcyclohexylamine. The higher is N,N-diallyl-1,4,4-trimethylcyclohexylamine. These are dissolved in ether, and gassed with dry hydrogen chloride until precipitation is complete. The precipitates are filtered and dried to yield N-allyl- 1,4,4-trimethylcyclohexylamine hydrochloride and N,N- diallyl 1,4,4 trimethylcyclohexylamine hydrochloride, respectively.

EXAMPLE 9 A reaction is run as described in Example 8, substituting 16.4 g. (0.20 mole) of propargyl chloride for the 24.2 g. of allyl bromide. The lower-boiling fraction is N- propargyl-l,4,4-trimethylcyclohexylamine, and the higherboiling fraction is N,N-dipropargyl-1,4,4-trimethylcyclohexylamine. N-propargyl-l,4,4-trimethylcyclohexylamine hydrochloride and N,N-dipropargyl-1,4,4-trimethylcyclohexylamine hydrochloride are made as described.

EXAMPLE 10 An 0.05-mole amount of l,4,4-trimethylcyclohexanol (Example 1) is dissolved in 27 ml. of 97% formic acid. This solution is added dropwise to a stirred solution of 300 ml. of concentrated sulfuric acid at C. After the addition is complete, stirring is continued for minutes, and the reaction mixture is poured on ice. The solid acid is filtered, dissolved in dilute potassium hydroxide, the solution is extracted with a small amount of chloroform, and the aqueous layer is acidified. The precipitate of l,4,4-trimethylcyclohexanecarboxylic acid is filtered and dried.

A mixture of 0.015 mole of 1,4,4-trimethylcyclohexanecarboxylic acid and 10 ml. (16.55 g., 0.139 mole) of thionyl chloride are refluxed two hours, then cooled to room temperature. The excess thionyl chloride is removed at reduced pressure, and the acid chloride residue is dissolved in 100 ml. of dry chloroform. This is cooled to 10 C., and ammonia gas is bubbled in for 10 minutes. Then the mixture is allowed to warm to room temperature and stir overnight. The solvent is evaporated in a vacuum, and the residue is dissolved in 100 ml. of benzene. The insoluble ammonium chloride is filtered, and the filtrate is concentrated to dryness to yield 1,4,4-trimethylcyclohexanecarboxamide.

A 200-ml. round-bottom flask is fitted with a Soxhlet extractor and charged with 1.56 g. of lithium aluminum hydride and 200 ml. of ether. The extractor cup is charged with 0.015 mole of 1,4,4-trimethylcyclohexancarboxamide, and the apparatus is operated overnight, stirring the flask contents with a magnetic stirrer. The reaction is cooled to room temperature and the excess lithium aluminum hydride is destroyed by cautiously adding about 5 ml. of water until the solids are white, and coagulated. The mixture is filtered, the solids are washed well with ether, and filtrate and washings are combined, dried with solid potassium hydroxide and then dried with anhydrous magnesium sulfate. Dry hydrogen chloride gas is bubbled into the ether solution until precipitation is complete. The precipitate is filtered and dried to yield l,4,4-trimethylcyclohexanemethylamine hydrochloride.

EXAMPLE 11 The use of anhydrous methylarnine gas in place of ammonia gas in the procedure of Example 10 yields N 1,4,4 tetramethylcyclohexanecarboxamide, which is reduced with lithium aluminum hydride by the procedure of the Example to yield N-1,4,4-tetramethycyclohexanemethylamine hydrochloride. I

EXAMPLE 12 The procedure of Example 10 is repeated, substituting 5 ml. of isobutyl methyl amine for the ammonia gas, dropping the liquid amine into the solution of the acid chloride in chloroform at 10 C. After warming to room temperature and stirring overnight, the chloroform is evaporated at reduced pressure. The residue is stirred in ml. of water, then filtered and dried to yield N-isobutyl- N-1,4,4-tetramethylcyclohexanecarboxamide. This compound is reduced by the procedure of Example 10 to yield N isobutyl N-1,4,4-tetramethylcyclohexanemethylamine hydrochloride.

EXAMPLE 13 A mixture of 3.6 g. of magnesium turnings, a small crystal of iodine, 11 ml. of anhydrous benzene and 1 ml. of absolute ethanol is heated. until reaction occurs. Heating is discontinued, and a mixture of 24.0 g. of diethyl malonate, 7.0 g. of absolute ethanol and 30 ml. of benzene is added dropwise at a rate which causes the reaction mixture to reflux. After addition is complete, the mixture is heated at reflux until the magnesium has dissolved. The excess ethanol is removed by azeotropic distillation with some of the benzene. A solution of 0.10 mole of 1,4,4 trimethylcyclohexanecarboxylic acid chloride in 30 ml. of benzene is added dropwise over a 50- minute period to this solution of ethoxymagnesiumdiethylmalonate. The reaction mixture is refluxed for an additional hour and then cooled in an ice bath. To the cold mixture is added 50 g. of ice followed by suflicient 10% sulfuric acid to cause two clear layers to appear. The layers are separated, and the aqueous layer is extracted with two 25-m1. portions of benzene. The extracts are combined with the organic layer, washed with 30 ml. of water, and dried with anhydrous magnesium sulfate. The benzene is removed by vacuum concentration at 40. A solution of 64 ml. of glacial acetic acid, 39 ml. of water and 7 ml. of concentrated sulfuric acid is added to the residue, and the mixture is heated at reflux for 7 hours. Then it is cooled and poured into 350 ml. of water. The mixture is extracted with two -ml. portions of ether, which are combined, dried with anhydrous magnesium sulfate, and vacuum concentrated to yield 1,4,4 trimethylcyclohexyl (1) methyl ketone.

A mixture of 14 g. of hydroxylamine hydrochloride, 65 ml. of anhydrous pyridine and 65 ml. of anhydrous ethanol is heated on a steam bath until a clear solution is obtained. To this is added 12.5 g. of 1,4,4 trimethylcyclohexyl (1) methyl ketone, and. the mixture is heated at reflux for 2 hours, then cooled. It is concentrated to dryness in a vacuum at 70 C., and the residue is suspended in ml. of water and stirred well. The solids are filtered and dried to yield 1,4,4 trimethylcyclohexyl (1) methyl ketone oxime.

A 7.8-g. amount of 1,4,4 trimethylcyclohexyl (1) methyl ketone oxime is added to a mixture of 3.3 g. of

9 lithium aluminum hydride in 150 ml. of anhydrous tetrahydrofuran, and the mixture is stirred and heated at reflux for 3 hours. It is cooled in an ice bath and the excess of lithium aluminum hydride is destroyed with a watertetrahydrofuran mixture. Several ml. of 10% sodium hydroxide solution is added to aid in the coagulation of the solids, which are removed by filtration, washed with 50 ml. of chloroform, and discarded. The filtrate, which includes the tetrahydrofuran solution and the chloroform solution, is saturated with dry hydrogen chloride and then concentrated to dryness in a vacuum at 50 C. The residue is placed in a separatory funnel and shaken with a mixture of 100 ml. of 10% sodium hydroxide and 300 ml. of ether.'The aqueous layer is discarded and the ether solution is dried over potassium hydroxide pellets. Dry hydrogen chloride is passed into the ether solution until precipitation is complete, and the resultant amine hydrochloride is filtered and dried. This crude salt is dissolved in water, treated with excess 50% sodium hydroxide solution, and the free amine is extracted with ether. The ether extract is dried over potassium hydroxide pellets, decanted, and hydrogen chloride is passed in until precipitation is complete. The precipitate is filtered and dried to yield a 1,4,4 tetramethy-lcyclohexanemethylamine hydrochloride.

' EXAMPLE 14 A solution of diethyl cadmium in benzene is prepared by adding 19.6 g. of powdered anhydrous cadmium chloride over a -minute period to 0.2 mole of ethyl magnesium bromide in 100 ml. of anhydrous ether at ice bath temperature. The mixture is heated at reflux with vigorous stirring for 30 minutes. Then the ether is removed by distillation on a steam bath and 65 ml. of benzene is added to the nearly dry, brown, pasty residue. Distillation is continued until the vapor temperature of the distillate reaches 61 C. An additional 100 ml. of benzene is added to the diethyl cadmium solution, and the solution is again heated to reflux. Heating is discontinued, vigorous stirring is begun, and a solution of 0.10 mole of 1,4,4 trimethylcyclohexanecarboxylic acid chloride in benzene is added as rapidly as the exothermic reaction will allow. Refluxing and stirring are continued for an additional 45 minutes. The reaction mixture is cooled in an ice bath and 200 g. of water and ice is added, followed by 150 ml. of 20% sulfuric acid. The benzene layer is separated and the aqueous layer is extracted with 75 ml. of benzene. The benzene solutions are combined, dried with anhydrous magnesium sulfate, and the benzene is removed by vacuum concentration at 50 to yield a residue of 1,4,4 trimethylcyclohexyl (1) ethyl ketone.

Use of this compound in the procedure of Example 13 yields 1,4,4 trimethylcyclohexyl (1) ethyl ketone oxime, which is reduced with lithium aluminum hydride by the procedure of that example to yield a-ethyl-1,4,4-

trimethylcyclohexanemethylamine hydrochloride.

EXAMPLE 15 To a solution of 27.4 g. of 1,4,4 trimethylcyclohexanecarboxylic acid chloride in 500 ml. of anhydrous ether under a nitrogen atmosphere is added, dropwise, 150 ml. of commercial 3M methyl magnesium bromide at a rate which maintains a gentle reflux. The reaction mixture is heated for 1 hour after addition, then cooled. To decompose the metal complex, 300 ml. of saturated ammonium chloride is added. The ether layer is separated and the aqueous layer is extracted with 100 ml. of chloroform. Thisextract is combined with the ether layer, and the mixture is dried with anhydrous magnesium sulfate and vacuum-concentrated to dryness at 35 C. The residue is steam-distilled until the distillate is no longer milky. After cooling, the steam-distillate is extracted with two 250-ml. portions of ether, which are combined, dried with anhydrous magnesium sulfate, and vacuum-concentrated to yield a,a,1,4,4 pentamethylcyclohexanemethanol.

A 35-ml. amount of concentrated sulfuric acid is added dropwise with cooling to hold the temperature below 10 C., to 160 ml. of acetonitrile. Then 18.2 g. of a,a-1,4,4-pentamethylcyclohexanemethanol is added. The temperature is raised to 48 C. and maintained at 48 C. for 45 minutes. The reaction mixture is allowed to cool to room temperature and is slowly poured into 1000 ml. of ice water. The solids which separate are filtered and dried to yield N-acetyl-a,a-1,4,4-pentamethylcyclohexanemethylamine.

A mixture of 2.0 g. of N-acetyl-a,u-l,4,4-pentamethylcyclohexanemethylamine, 10 g. of potassium hydroxide and 40 ml. of methyl is heated at 225 C. in a sealed tube for 18 hours, then cooled. The tube contents are added to 100 ml. of water, and the mixture is extracted with two 50-ml. portions of ether. The extracts are com bined, dried with potassium hydroxide pellets, and dry hydrogen chloride is bubbled in until precipitation is complete. The precipitate is filtered and dried to give a crude salt. This is dissolved in ml. of water and treated with an excess of 50% sodium hydroxide, then extracted with two SO-ml. portions of ether. The ether extracts are combined, dried with potassium hydroxide pellets, and hydrogen chloride is bubbled in until precipitation is complete. The precipitate of 11,0:-1,4,4-pentamethylcyclohexanemethylamine hydrochloride is filtered and dried.

EXAMPLE 16 To a mixture of 1.5 g. of lithium aluminum hydride in ml. of anhydrous diethylene glycol, dimethyl ether is added 4.0 g. of N-acetyl-a,u-1,4,4-pentamethylcyc1ohexanemethylamine (Example 15). The reaction mixture is stirred and heated at reflux for 3 hours, then cooled in an ice bath. The excess lithium aluminum hydride is decomposed by adding wet diethylene glycol, dimethyl ether. Several ml. of 10% sodium hydroxide is added to coagulate the precipitate, which is filtered and washed with 50 ml. of ether. The filtrate is treated with dry hydrogen chloride until no additional precipitate forms. This is filtered, dissolved in 100 ml. of water, and an excess of 50% sodium hydroxide is added. The mixture is extracted with three 30-ml. portions of ether, and the ether extracts are combined, dried with potassium hydroxide pellets, and treated with hydrogen chloride until precipitation is complete. This precipitate is filtered and dried to yield N-ethyl cam-1,4,4 pentamethylcyclohexanemethylamine hydrochloride.

EXAMPLE 17 Enough methanol (about ml.) is added to a mixture of 3.16 moles of freshly redistilled methyl vinyl ketone, 3.16 moles of Z-methylbutanal, also freshly redistilled, and 320 ml. of water, so that a homogeneous mixture is formed. A 2-liter round-bottom flask is fitted with a stirrer, dropping funnel, condenser, thermometer and gas inlet, and charged with 60 ml. of methanol and 12 g. of potassium hydroxide pellets. The: air is swept from the flask with a stream of nitrogen, and the mix ture in the dropping funnel is run in slowly, with good stirring. The temperature rises to 75 C. quite rapidly. An ice bath is applied to the flask, and the temperature is brought down to 30-35 C. for the major portion of the addition. After addition is complete, the reaction mix ture is heated at 75 C., with stirring, for 1 hour, then cooled. It is extracted with five 250-ml. portions of ether. The ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and the ether is removed by vacuum concentration. The residue is purified by distillation at reduced pressure to yield 4-ethyl-4- methyl-Z-cyclohexen-l-one.

When 3.16-mole amounts of 2-methylpentanal and of 2,3-dimethylbutanal are substituted for the 3.16 moles of 2-methylbutanal in this procedure, 4-propyl-4-methyl- 2 cyclohexen-l-one and 4-isopropyl-4-methyl2-cyclohexen-l-one, respectively, are formed.

A mixture of 0.10 mole of 4-ethyl-4-methyl-2-cyclohexen-l-one, 100 ml. of absolute ethanol and 0.5 g. of

% palladium on charcoal catalyst is hydrogenated at 30 p.s.i.g. and room temperature in a low pressure Parr hydrogenation apparatus until no more hydrogen is absorbed. The catalyst is filtered, the ethanol is removed by vacuum concentration, and the residue is distilled at reduced pressure to yield 4-ethyl-4-methylcyclohexanone.

When 0.10-mole amounts of 4-propyl-4-rnethyl-2-cyclohexen-l-one and 4-isopropyl-4-methyl-2cyclohexen-l-one are substituted for the 0.10 mole of 4-ethyl-4-methyl- 2cyclohexen-l-one in this procedure, 4-propyl-4-methylcyclohexanone and 4-isopropyl-4-methylcyclohexanone, respectively, are formed.

When 0.10-mole amounts of 4-ethyl-4-methylcyclohexanone, 4 propyl-4-methylcyclohexanone and 4-isopropyl-4-methylcyclohexanone are substituted for the 12.6 g. (0.10 mole) of 4,4-dimethylcyclohexanone in the procedure of Example 1, 4-ethyl-1,4-dimethylcyclohexanol, 4-propyl-1,4-dimethylcyclohexanol and 4-isopropyl-l,4- dimethylcyclohexanol, respectively, are formed. Continuation of the procedure of Example 1, substituting 0.05-mole amounts of these cyclohexanols for the 7.1 g. (0.05 mole) of l,4,4-trimethylcyclohexanol, yields N- acetyl-4-ethyl-1,4-dimethylcyclohexylamine, N-acetyl 4- propyl-1,4-dimethylcyclohexylamine and N-acetyl-4-isopropyl-1,4-dimethylcyclohexylamine, respectively. Finally, continuing the procedure of that example, substitution of 2 g. amounts of these compounds for the 1.5 g. of N acetyl 1,4,4 trimethylcyclohexylamine yields 4- ethyl 1,4 dimethylcyclohexylamine hydrochloride, 4- propyl-1,4-dimethylcyclohexylamine hydrochloride and 4- isopropyl-1,4-dimethylcyclohexylamine hydrochloride, respectively.

EXAMPLE 18 When 0.05-mole amounts of 4-ethyl-1,4-dimethylcyclohexanol, 4-propyl-1,4-dimethylcyclohexanol and 4-isoproply-1,4-dimethylcyclohexanol (see the preceding example) are substituted for the 0.05 mole of 1,4,4-trimethylcyclohexanol in the procedure of Example 10, 4-ethyl-1, 4-dimethylcyclohexanecarboxylic acid, 4-propyl 1,4-dimethylcyclohexanecarboxylic acid and 4-isopropyl-1,4- dimethylcyclohexanecarboxylic acid, respectively, are formed.

Continuation of that procedure, using 0.015-mole amounts of these compounds in place of the 0.015 mole of l,4,4-trimethylcyclohexanecarboxylic acid, yields 4-ethyl- 1,4-dimethylcyclohexanecarboxylic acid chloride, 4-propyl-1,4-dimethylcyclohexanecarboxylic acid chloride and 4-isopropyl-1,4-dimethylcyclohexanecarboxylic acid chloride, respectively, which are converted to 4-ethyl-1,4-dimethylcyclohexanecarboxamide, 4-propyl-1,4-dimethylcyclohexanecarboxamide and 4-isopropyl-1,4-dimethylcyclohexanecarboxamide, respectively. Substitution of 0.015- mole amounts of these compounds for the 0.015 mole of 1,4,4 trimethylcyclohexanecarboxamide in the lithium aluminum hydride reduction step of that procedure yields 4-ethyl-l,4 dimethylcyclohexanemethylamine hydrochloride, 4-propyl-1,4 dimethylcyclohexanemethylamine hydrochloride and 4-isopropy1- 1,4 dimethylcyclohexanemethylamine hydrochloride, respectively.

EXAMPLE 19 A suitable flask equipped with stirrer, thermometer, reflux condenser, dropping funnel and cooling bath is charged with 2.0 moles of l,4,4-trimethylcyclohexylamine. A 37% aqueous solution of formaldehyde, 2.05 moles, is added slowly with stirring, maintaining the temperature below 40 C. After addition is complete, the reaction is cooled to room temperature, and powdered potassium hydroxide, 10 g., is added to aid in separation of the water. The organic layer is separated, dried over potassium hydroxide pellets, and distilled at reduced pressure to yield N-(1,4,4-trimethylcyclohexyl-1-)azomethine.

12 EXAMPLE 20 A flask equipped with a Dean-Stark Water separator is charged with 0.10 mole of aa-1,4,4-pentamethylcyclohexanemethylamine, 15.4 g. (0.10 mole) of freshly distilled benzaldehyde, and 50 ml. of toluene. The reaction is heated at reflux for 45 hours. The toluene is evaporated in a vacuum to yield a residue of N-benzylidene-a,a-1,4,4- pentamethylcyclohexanemethylamine.

EXAMPLE 21 A mixture of 0.10 mole of 4-ethyl-1,4-dimethylcyclohexylamine and 9.87 g. (0.10 mole) of 38% hydrochloric acid in 100 ml. of water is concentrated in a vacuum at 60 C. The residue is dried thoroughly in a vacuum oven. It is 4-ethyl-l,4-dimethylcyclohexylamine hydrochloride.

EXAMPLE 22 A mixture of 0.10 mole of 1,4,4-trimethylcyclohexanemethylamine and 0.10 mole of glacial acetic acid in 100 ml. of water is concentrated in a vacuum at 60? C. The residue is dried well, and is 1,4,4-trimethylcyclohexanemethylamine acetate.

EXAMPLE 23 A mixture of 0.10 mole of N-1,4,4-pentamethylcyclohexanemethylamine and 0.10 mole of lactic acid in 75 ml. of absolute ethanol is concentrated in a vacuum at 45 C., and then dried Well. The compound is N'ot-1,4, 4-pentamethylcyclohexanemethylamine lactate.

EXAMPLE 24 A solution of 0.20 mole of (1,0:-1,4,4-pentamethylcyclohexanemethylamine hydrochloride in ml. of water is added to a solution of 0.10 mole of pamoic acid disodium salt in 500 ml. of water. (Pamoic acid is also called 4,4- methylene-bis-(3-hydroxy-2-naphthoic acid).) The resulting precipitate is filtered, washed well with water, and dried to yield ega-l,4,4-pentamethylcyclohexanemethylamine pamoate.

The preceding examples can be repeated substituting equivalent amounts of appropriate starting materials to obtain other compounds of this invention including those listed hereinbefore.

The compounds of Formula 1 above can be administered in the antiviral treatment according to this invention by any means that effects contact of the active ingredient compound with the site of virus infection in the body. It will be understood that this includes the site prior to infection setting in as well as after. For example, administration can be parenterally, that is subcutaneously, intravenously, intramuscularly, or intraperitoneally. Alternatively or concurrently, the compounds are effective on administration by the oral route. Since they are particularly effective against respiratory infections such as viral influenza and viral pneumonia, administration can be by vapor or spray through the mouth or nasal passages.

The compounds within the scope of this invention are valuable for viral prophylaxis, as well as for therapeutic treatment.

The dosage administered will be dependent upon the virus being treated, the age, health and weight of the recipient, the extent of infection, kind of concurrent treatment if any, frequency of treatment, and the nature of the effect desired. Generally, a daily dosage of active ingredient compound will be from about 0.05 to 25 milligrams per kilogram of body weight, although lower or higher amounts can be used. Ordinarily, from about 0.1 to 10 milligrams per kilogram per day, in one or more 13 applications per day, is effective to obtain the desired result.

The active ingredient of Formula 1 can be employed in useful compositions according to the present invention in such dosageforrns as tablets, capsules, powder packets, or liquid solutions, suspensions, or.elixirs, fororal administration or liquid solutions for parenteral use, and in certain cases, suspensions for parenteral use (except intravenous). In such compositions the active ingredient will ordinarily always be present in an amount of at least 0.5 by weight based on the total weight of the composition and not more than 90% by weight.

Besides the active ingredient of Formula 1 the antiviral composition will contain a solid or liquid non-toxic pharmaceutical carrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, the solid carrier is a capsule which can be of the ordinary gelatin type. In the capsule will be from about 30-60% by weight of acompound of Formula 1 or 2 and 70-40% of a carrier. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed. These capsules, tablets and powders will generally constitute from about 5% to about 95% and preferably from 25% to 90% by weight. These dosage forms preferably contain from about 1 to about 500 milligrams of active ingredient.

The pharmaceutical carrier can, as previously indicated, be a sterile liquid such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, and the like. In general, water, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are preferred liquid carriers, particularly for injectable solutions. Sterile injectible solutions suchas saline will ordinarily contain from about 0.1 to and preferably about 0.5 to 5% by weght of the active ingredient.

As mentioned above, oral administration can he in a suitable suspension or syrup, in which the active ingredi ent ordinarily will constitute from about 0.05 to 10% and preferably about 0.1 to 5%, by weight. The pharmaceutical carrier in such composition can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in Remingtons Practice of Pharmacy by E. W. Martin and E. F. Cook, a well known reference text in this field.

In addition to the exemplary illustrations above, the following examples further explain the present invention:

EXAMPLE 26 A large number of unit capsules are prepared by filling standard #3 two-piece hard gelatin capsules weighing about 50 milligrams each with 10 milligrams of powdered 1,4,4-trimethylcyclohexylamine, hydrochloride, 237 milligrams of lactose and 2.5 milligrams of Cab-o-sil.

EXAMPLE 27 Example 26 is repeated except that soft gelatin capsules are used and the powdered 1,4,4-trimethylcyclohexylamine is first dissolved in soya bean oil.

EXAMPLE 28 Example 26 is repeated except that the dosage unit is 10 milligrams of active ingredient, 1 milligram of gelatin, 0.3 milligram of magnesium stearate and 20 milligrams of mannitol, mixed and formed into a tablet by a conventional tableting machine. Slow release pills or tablets can also be used, by applying appropriate coatings. A sugar coating may be applied to increase palatability.

EXAMPLE 29 A parenteral composition suitable for administration by injection is prepared by stirring 0.5% by weight of the active ingredient of Example 26 in sterile aqueous 0.9% saline.

A large variety of compositions according to this invention can thus readily be made by substituting other compounds of this invention, and including specifically but not limited to compounds of this invention that have specifically been named hereinbefore. The compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin and Cook text mentioned above.

The compounds of this invention are particularly effective against swine influenza. An important embodiment of this invention therefore is the control of this infection by incorporating an active ingredient compound in the diet of the affected animal. For most purposes, an amount of active compound will be used to provide from about 0.0001 to 0.1% by weight of the active compound based on the total weight of feed intake. Preferably, from 0.001% to 0.02% by weight will be used.

In a related aspect, novel and useful compositions are provided by this invention which comprise at least one active ingredient compound within the scope of this invention in admixture with an animal feed. Descriptions of suitable feeds can be found in the book Feeds and Feeding by Frank B. Morrison, published by the Morrison Publishing Company of Ithaca, N.Y., 1948, 21st edition. The selection of the particular feed is within the knowledge of the art and will depend of course on the animal, the economics,,natural materials available, the surrounding circumstances and the nature of the effect desired, as will be readily understood.

Particularly important composition according to this feature of the invention is a concentrate, suitable for preparation and sale to a farmer or livestock grower for addition to the animals feedstutfs in appropriate proportion. These concentrates ordinarily comprise about 0.5% to about by weight of the active ingredient compound together With a finely divided solid, preferably flours, such as wheat, corn, soya bean and cottonseed. Depending on the recipient animal, the solid adjuvant can be ground cereal, charcoal, fullers earth, oyster shell and the like. Finely divided attapulgite and bentonite can be used, these latter materials also acting as solid dispersing agents.

The feed compositions, as well as the just described concentrates, can additionally contain other components of feed concentrates or animal feeds, as will be readily understood. Other particularly important additives include proteins, carbohydrates, fats, vitamins, minerals, antibiotics, etc.

The following example will further illustrate this aspect of this invention:

EXAMPLE 30 A feed for pigs is prepared as follows:

There is added to the pigs diet a concentration of 50% of 1,4,4-trimethylcyclohexylamine hydrochloride as the active ingredient and 50% by weight corn flour, in an amount that provides 0.015% by weight of the active ingredient based on the total diet.

The disclosure herein should not be taken as a recommendation to use the disclose-d invention in any way without full compliance with US. Food and Drug Laws and 15 other laws and governmental regulations which may be applicable.

The above and similar examples can be carried out in accordance with the teachings of this invention, as will be readily understood by persons skilled in the art, by substitution of components and amounts in place of those specified. Thus, the foregoing detailed description has been given for clearness of understanding only and no unnecessary limitations are to be understood therefrom.

I claim:

1. A compound of the formula CH R Where R is selected from the group consisting of methyl, ethyl,

propyl and isopropyl;

X and Y are each selected from the group consisting of hydrogen, methyl, and ethyl;

n is selected from the group consisting of and 1;

R is selected from the group' consisting of hydrogen, alkyl of 1 through 4 carbon atoms, alkenyl of 3 through 4 carbon atoms with the unsaturated bonding in other than the 1-position and alkynyl of 3 through 4 carbon atoms with the unsaturated bonding in other than the 1-position; and

R is selected from the group consisting of R and formyl;

and nontoxic salts of said compounds.

2. A compound of claim 1 wherein R and R are each an alkyl of 1 through 4 carbon atoms and n is 1.

3. A compound of claim 1 wherein X and Y are each methyl or ethyl and n is 1.

4. 1,4,4-trimethylcyclohexylamine hydrochloride.

5. N,N-1,4,4-pentamethylcyclohexylamine hydrochloride. l 6. N-1,4,4-tetramethylcyclohexylamine hydrochloride.-

7. 1,4,4-trimethylcyclohex-anemethylamine hydrochloride.

8. N,N-1,4,4-pentamethylcyclohexamethylamine hydrochloride.

9. N l,4,4-tetramethylcyclohexanemethylamine hydrochloride.

10. 4-ethyl 1,4 dimethylcyclohexylamine hydrochloride.

11. 4-ethyl-N,N 1,4 tetramethylcyclohexylamine hydrochloride.

12. 4-ethyl-N-1,4-trimethylcyclohexylamine hydrochloride.

13. a-l,4,4-tetramethylcyclohexanemethylamine hydrochloride.

14. N,N-u-1,4,4 hexamethylcyclohexanemethylamine hydrochloride.

15. a t-1,4,4-pentamethylcyclohexanemethylamine hy drochloride.

16. N,N 0:,0: 1,4,4 heptamethylcyclohexanemethylamine hydrochloride.

References Cited M. 'Protiva et aL: Polymethylcyclohexylamine-neue, hypotensiv wirksame Substanzen, Experientia, 15 (1959), pp. 5455.

CHARLES E. PARKER, Primary Examiner.

P. IVES, Assistant Examiner. 

